Throughout this application various publications are referred to in parenthesis. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
The field of infectious diseases is currently in crisis given that: 1) there is an increasing prevalence of infections with highly resistant microorganisms that are not susceptible to existing antimicrobial agents; 2) many infections occur in immunosuppressed individuals in whom standard antimicrobial therapy is not very effective; and 3) there is a dearth of new anti-microbials drugs in the development pipeline as evidenced by the paucity of new drugs in the past decade. In this environment new approaches are needed to antimicrobial therapy in general and to AIDS-associated opportunistic infections therapy in particular.
Fungal diseases in particular are notoriously difficult to treat and currently constitute a major clinical problem in immunosuppressed patients (e.g., HIV-infected individuals, cancer patients, organ transplant recipients) because antifungal drugs do not eradicate the infection in the setting of severe immune dysfunction (7-9). Most life-threatening invasive fungal infections occur in severely immunosuppressed individuals (7).
Cryptococcus neoformans (CN) is a major fungal pathogen that causes life-threatening meningoencephalitis in 6-8% of patients with AIDS. Cryptococcal infections in immunosuppressed patients are often incurable (8,9). Immunotherapy of CN infection with passive antibody is being evaluated (10). However, with passive antibody treatment, a loss of effectiveness can occur when the antibody is administered in amounts greater than an optimally protective amount (45). Another fungal species, Histoplasma capsulatum (HC) is the most common causes of fungal pneumonia (60).
Another example of an important pathogen is Streptococcus pneumoniae, which is an important cause of community-acquired pneumonia, meningitis, and bacteremia. The problem of pneumococcal disease is increased by drug resistance (73). Furthermore, there is an increased prevalence of invasive pneumococcal infections in patients with immune impairment caused by chemotherapy or immune suppression in the setting of organ transplantation or HIV infection (74). Thus, there is an urgent need for new approaches to anti-pneumococcal therapy.
Furthermore, the 21st century has witnessed a global outbreak of SARS and the introduction of monkey pox virus into the United States. In this environment, new approaches to antimicrobial therapy are needed. Specifically new strategies are required that can translate into the rapid development of new antimicrobial agents. Current strategies for the development of antimicrobial drugs and vaccines take many years to yield clinically useful products.
Radioimmunotherapy (RIT) is a therapeutic modality which uses antibody-antigen interaction and utilizes antibodies radiolabeled with therapeutic radioisotopes to deliver lethal doses of radiation to cells in cancer treatment (40). Radiolabeled antibodies provide valuable alternatives to cancer treatment with chemotherapy or external radiation beam by selectively delivering lethal doses of radiation to cancerous cells. There is an abundance of published information on the interaction of radiolabeled antibodies with target cancer cells, surrounding tissue and major organs obtained from laboratory and clinical studies (41-43). Radioisotopes with decay characteristics allowing treatment of relatively large lesions (up to several cm in diameter), or, on the contrary, single cell disease, are now available. Although RIT of cancer has been studied for almost 20 years, during this time there has been no attempt to apply RIT to the field of infectious diseases.
Radiation also possesses microbicidal properties and γ-irradiation is routinely used for sterilization of medical supplies and certain foods. Ionizing radiation such as γ-rays, β- and especially α-particles from external sources can kill different strains of bacteria and fungi such as E. coli, M tuberculosis, and C. neoformans (1-3). However, many fungi manifest extreme radioresistance to external gamma radiation relative to other microorganisms and mammalian cells (1, 2, 55, 56, 58). For example, a dose of several thousands Gy is required to achieve 90% cell killing of fungal cells whereas the lethal dose for mammalian cells in only a few Gy. The mechanisms responsible for these differences are not well understood but could involve more efficient mechanisms of DNA repair by fungi when the damage is caused by gamma rays. A dramatic example of the radioresistance of fungi is provided by reports of numerous melanotic fungal species colonizing the walls of the damaged nuclear reactor at Chernobyl in extremely high radiation fields (59).
In order to realize the full benefits of ionizing radiation as an anti-infective treatment, it is important to target the radiation to the sites of infection to minimize toxicity to the host. In contrast to tumor cells, infectious agents such as fungal and bacterial cells are antigenically very different from host tissue and thus provide the potential for abundant pathogen-antibody interactions with low cross-reaction with tissue. In this regard, pathogen-specific antibodies have been used experimentally for the diagnosis of certain infectious diseases, as exemplified by the application of 99mTc-Fab′ fragments directed against Pneumocystis carinii to visualize the site of infection in patients (5) and by the visualization of tuberculomas in a rabbit model with an antibody to M. bovis (BCG) (6). The successful detection of infection with radiolabeled antibodies indicates that antigen-antibody interactions can be used to deliver radionuclides to microorganisms in vivo. However, since certain types of microorganisms (e.g., bacterium Deinococcus radiodurans, and yeasts Cryptococcus neoformans, Saccharomyces ellipsoideus and Saccharomyces cerevisiae) are extremely resistant to gamma radiation (2, 54-56), it has not been apparent whether infectious microorganisms are susceptible to particulate radiation.